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Immune Desensitization Allows Pediatric Blood Group Incompatible Kidney Transplantation

Stojanovic, Jelena MBBS MRCPH1; Adamusiak, Anna PhD2; Kessaris, Nicos MSc, FRCS1,2,3; Chandak, Pankaj BSc, MRCS, FRAS2; Ahmed, Zubir MSc, MRCS2; Sebire, Neil J. MD4; Walsh, Grainne MSc1; Jones, Helen E. MBBS, MRCPCH1; Marks, Stephen D. MD, FRCPCH3; Mamode, Nizam MD, FRCS1,2,3

doi: 10.1097/TP.0000000000001325
Original Clinical Science—General: Outcomes
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Background Blood group incompatible transplantation (ABOi) in children is rare as pretransplant conditioning remains challenging and concerns persist about the potential increased risk of rejection.

Methods We describe the results of 11 ABOi pediatric renal transplant recipients in the 2 largest centers in the United Kingdom, sharing the same tailored desensitization protocol. Patients with pretransplant titers of 1 or more in 8 received rituximab 1 month before transplant; tacrolimus and mycophenolate mofetil were started 1 week before surgery. Antibody removal was performed to reduce titers to 1 or less in 8 on the day of the operation. No routine postoperative antibody removal was performed.

Results Death-censored graft survival at last follow-up was 100% in the ABOi and 98% in 50 compatible pediatric transplants. One patient developed grade 2A rejection successfully treated with antithymocyte globulin. Another patient had a titer rise of 2 dilutions treated with 1 immunoadsorption session. There was no histological evidence of rejection in the other 9 patients. One patient developed cytomegalovirus and BK and 2 others EBV and BK viremia.

Conclusions Tailored desensitization in pediatric blood group incompatible kidney transplantation results in excellent outcomes with graft survival and rejection rates comparable with compatible transplants.

Blood group incompatible transplantation (ABOi) in children is rare as pretransplant conditioning remains challenging. The authors report the results of 11 pediatric ABOi and tailored desensitization results in excellent outcomes with graft survival and rejection rates comparable with compatible transplants

1 Department of Pediatric Nephrology and Transplantation at Evelina London Children's Hospital, London, United Kingdom.

2 Department of Transplantation at Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom.

3 Department of Pediatric Nephrology and Transplantation at Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

4 Department of Histopathology at Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

Received 18 November 2015. Revision received 30 April 2016.

Accepted 3 May 2016.

N.M. acknowledges financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King’s College Hospital NHS Foundation Trust.

The authors declare no conflict of interest.

J.S. did the data acquisition and analysis and wrote the article. A.A. did the data acquisition and analysis and reviewed the article. N.K. revised the work and reviewed the article. P.C. did the data acquisition and reviewed the article. Z.A. did the data analysis and reviewed the article. N.J.S. contributed to the data acquisition and review of the article. G.W. revised the work and reviewed the article. H.E.J. revised the work and reviewed the article. S.D.M. revised the work and reviewed the article. Nizam Mamode designed the work, interpreted the data and reviewed the article.

Correspondence: Nizam Mamode, Department of Transplant Surgery, Renal Offices, 6th Floor, Borough Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom. (nizam.Mamode@gstt.nhs.uk).

Over the last decade, blood group incompatible transplantation (ABOi) has become almost routine in the adult setting. Historically, desensitization strategies have relied on splenectomy and plasmapheresis.1,2 More recently, a combination of B cell depletion with rituximab, antibody removal with immunoadsorption (IA) or plasmapheresis, and triple maintenance immunosuppression, including calcineurin inhibitor (tacrolimus), an antiproliferative agent (mycophenolate mofetil), and steroids has been used. Several groups have reported very good long-term graft outcomes comparable to compatible transplants.3 We have recently reported good short-term and long-term graft outcomes comparable with compatible transplants using a tailored desensitization protocol with no routine postoperative antibody removal in adults,4 and there are other reports of minimizing desensitisation in low titer patients.5 Furthermore, there is evidence that blood group titers are lower in children.6

Although encouraging data are emerging for adult renal recipients, ABOi transplantation in children is still rare.7 This may be due to (1) technical difficulties when administering plasmapheresis in children (difficult vascular access, ie, smaller caliber veins, smaller extracorporeal blood volume, risk of coagulopathy)8,9; (2) concerns about the potential increased risk of rejection as the immune system differs in children (immune system matures in puberty, children are born with a fully functioning thymus, have a higher proportion of naive T cells, fewer antigen-specific T cell precursors with impaired toll-like receptor signalling due to relative deficiency of CD40L)10,11; and finally, (3) because of the potentially higher risk of infectious complications because only 50% of children are EBV seropositive by the age of 8 years,12 and only 40% of teenagers in developing countries are cytomegalovirus (CMV) seropositive.13

Although numerous centers have reported their experience and desensitization protocols in adults,14 there are few reports of ABOi transplantation in children.15,16 The youngest reported cohort of children had a mean age at transplant 11.1 years17; our cohort reports patients with a mean age at transplant of 9 years with the youngest being only 2 years. In an attempt to minimize the risks described above, we have adopted a tailored desensitisation strategy for ABOi in children, with no routine posttransplant antibody removal, and here report our outcomes from the largest 2 pediatric transplant centers in the United Kingdom.

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MATERIALS AND METHODS

Eleven children underwent ABOi renal transplantation at Evelina London Children's Hospital and Great Ormond Street Hospital for Children National Health System Foundation Trust between August 2009 and February 2015.

Our previously described adult-tailored desensitization strategy4 was adopted and used for all children (Figure 1). The approach is based on the baseline antihemagglutinin titers. All patients with titers of 1 or more in 8 received rituximab (375 mg/m2) 1 month before transplant and basiliximab on days 0 and 4. When the titers were 1 or more in 64 patients, IA was used, whereas those patients with titers of 1 in 32 or 1 in 16 received double filtration plasmapheresis (DFPP). The aim was to reduce the titers to 1 or less in 8 at the time of transplant. Antibody removal was performed on consecutive days before transplant. We expect a fall of 2 dilutions in the titers with each session of DFPP/IA. Patients with titers of 1 in 8 received rituximab with no antibody removal. Those with titers of 1 or less in 8 received basiliximab without rituximab or antibody removal. Triple maintenance immunosuppression was used in all patients with tacrolimus and mycophenolate mofetil starting 1 week before the surgery and steroids on the day of the operation.

FIGURE 1

FIGURE 1

Patients undergoing ABOi were compared with 50 randomly selected patients undergoing blood group compatible (ABOc) pediatric transplants performed during the same period. Randomization was performed using the automatic function in “Microsoft Office Excel 2003.” There was no difference in posttransplant immunosuppressive regimens between the groups. We aim for tacrolimus levels of 8 to 12 ng/mL in the first 2 weeks posttransplant and 5 to 7 ng/mL from month 3 onward. Steroids are weaned over a 6-month period.

Three ABOi patients had previous renal transplants that failed and were undergoing a second kidney transplant. One of these received intravenous immunoglobulin (0.5 g/kg) 1 day before transplantation because he had donor-specific antibodies (HLA A24, B62, Cw9, MFI 9202).

No patient received routine postoperative antibody removal; our policy is to intervene when there is a titer rise of 2 dilutions or more or association with biochemical or histological evidence of graft dysfunction.

Rejection episodes were defined as those requiring treatment after histological confirmation according to the Banff criteria (initially 2007 and then 2013). Our policy is to perform a protocol biopsy 3 months after transplantation.

Anti-A and anti-B antibody titers were measured by the indirect antiglobulin test using gel cards (DiaMed ID-Card) at a single laboratory. Total immunoglobulin load (IgG and IgM) was used to determine the desensitisation protocol. For IA, we used “Glycosorb (Glycorex Transplantation, Sweden)” columns. We measured titers weeks 1 and 2, and months 1 and 3 posttransplant.

Estimated glomerular filtration rate (eGFR) was calculated using a bedside Schwartz formula (constant k = 34, creatinine in μmol/L) and reported in ml/min/1.73 m2. Estimated glomerular filtration rate at 3, 6, and 12 months posttransplant and at the last follow-up (February 2016) were recorded. Acute rejection rates and infectious complications within the first 12 months posttransplant in the 2 groups were compared.

The log-rank test was used to calculate rejection free graft survival, whereas an independent sample t test was performed to compare graft outcomes between the groups (P < 0.05 statistically significant).

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RESULTS

Eleven pediatric patients, with a mean age 9 years (SD, 4) underwent a living related ABOi kidney transplant. These were compared with 50 ABOc pediatric transplants performed during the same period (Table 1). Blood group incompatibility, baseline antibody titers before transplant, cause for end-stage renal disease, tailored desensitization strategies, weight, and age at time of transplant are shown in Table 2.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

The mean follow-up period for the ABOi group was 35 months (range, 5-76 months; SD, 22 months) and for the ABOc group was 28 months (range, 5-70 months; SD, 16 months). The difference in the follow-up periods between the groups was not statistically significant (P = 0.258).

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Immune Desensitization Strategy

Ten patients received rituximab 4 weeks before transplant. One patient had a baseline titer of 1 in 4 and therefore did not receive any treatment before surgery. Two patients with titers 1 in 8 received rituximab without any apheresis. Six patients needed DFPP with a mean number of sessions 2.3 per patient. The difference in the number of DFPP sessions received by patients who had the same baseline titers (patients 2 and 3) can be explained by our aim to continue with DFPP until the titer is 1:8 or less; some patients therefore required more sessions than others despite having the same baseline titers. Two patients with baseline titers 1 or more in 64 received IA (the patient with titers of 1 in 64 received 3 sessions and the patient with titers of 1 in 128 had 4 sessions of IA). Three patients were undergoing a second kidney transplant. One of these had donor-specific antibodies and received a dose of intravenous immunoglobulin in addition to rituximab and DFPP before transplant. Another renal transplant recipient received eculizumab 10 hours after the transplant to treat early recurrence of atypical hemolytic-uremic syndrome which was confirmed histologically and biochemically (rise in creatinine and lactate dehydrogenase and fall in platelets and hemoglobin); this patient lost the first graft (which was an en bloc kidney transplant) due to thrombosis. The donor specific antibodies were negative when tested on 6 separate occasions in the first month posttransplant in this patient.

There were no bleeding complications associated with administration of apheresis in any patients. Two of 6 patients who needed DFPP received a dose of fibrinogen on the day of transplant to correct mild coagulopathy.

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Patient and Graft Survival

Death-censored graft survival at follow-up was 100% in ABOi and 98% in ABOc (1 patient lost the graft due to antibody mediated rejection). One patient from the ABOi group died with a functioning graft 5 months after the transplant from withdrawal of treatment following line sepsis and gastrointestinal failure. This patient did not require any pretransplant desensitization because her baseline titers were 1 in 4; she was a complex high-risk transplant due to severe renovascular disease, and the only option for this patient, who was running out of access for dialysis, was a living related ABOi renal transplant. At the last follow-up, the median eGFR in the ABOi group was 61 mL/min per 1.73 m2 (range, 27-77 mL/min per 1.73 m2). The patient with the lowest eGFR was the patient who developed early rejection. The difference in eGFR between ABOc and ABOi patient groups at 3, 6, 12 months posttransplant, and at the last follow up were not statistically significant (74 vs 55; P = 0.086; 73 vs 54; P = 0.136; 70 vs 57; P = 0.110; 61 vs 61; P = 0.967; shown in Table 3).

TABLE 3

TABLE 3

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Acute Rejection

In the ABOi group, 1 patient (8%) developed acute T cell–mediated rejection (Banff 2007: t0 v1 i2 co0 ct0 cg0 mm0 cv0 ah0 pitch C4d0) 2 weeks after the transplant successfully treated with antithymocyte globulin (following a lack of response to IV methylprednisolone). This patient received rituximab as part of desensitization strategy. There was no histological evidence of rejection in the other 9 patients who had a total of 19 biopsies (4 protocols and 15 “for cause” biopsies) during the study period. In the ABOc group, 12 patients (24%) had a biopsy proven acute T cell–mediated rejection. The difference in rejection-free graft survival between the ABOi and ABOc groups in the first 12 months posttransplant was not statistically significant (P = 0.409; Kaplan-Meier survival curve) as shown in Figure 2.

FIGURE 2

FIGURE 2

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Infectious Complications

Three patients in ABOi group developed viremia in the first 12 months posttransplant: 1 CMV and BK and 2 EBV and BK. The patient with CMV and BK had no evident CMV disease and was both CMV and BK negative at last follow-up 4 years posttransplant. All viremias were controlled with reduction of immunosuppression. This management did not precipitate clinically evident or histologically confirmed rejection episodes. One of the patients who developed EBV and BK was the patient who received additional immunosuppression immediately posttransplant as she was treated with eculizumab after early recurrence of hemolytic-uremic syndrome (heterozygous for complement factor I c.1216C > T,p.Arg406Cys with antiFactor H antibodies). There was no histological evidence of BK nephropathy in any of the patients in both groups. Twenty-one patients in the control group became seropositive or reactivated CMV, BK, or EBV. The difference in viremias between the 2 groups was not statistically significant (P = 0.365).

None of the patients in the ABOi group required admission to hospital for sepsis although 1 patient died, as noted above, with suspected line sepsis after gastrointestinal failure.

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Posttransplant Titers and Removal of Antibodies

We did not perform routine removal of antibodies posttransplant. One patient had a rise in titers of 2 dilutions 1 week after the transplant that was associated with a mild rise in creatinine that was treated with 1 IA session. In the remaining 10 patients, the titers remained low and did not return to pretransplant baseline levels during the follow-up period. The titer dilutions at baseline, weeks 1 and 2, and months 1 and 3 posttransplant are shown in Figure 3.

FIGURE 3

FIGURE 3

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DISCUSSION

This is the first report in the literature of blood group incompatible kidney transplantation in children using a tailored desensitization strategy. This study demonstrates the short-term and long-term graft outcomes, as well as the rejection rates, to be comparable with compatible transplants. We also report a low risk of viral infectious complications. Tailored pretransplant conditioning minimizes desensitization with each patient receiving specific treatment based on their baseline titers. We acknowledge the fact that DFPP can be associated with a higher risk of bleeding. However, we estimated that patients with lower titers (ie, less than 1 in 64) would need only a few sessions of DFPP, which would allow correction of any mild coagulopathy, whereas the use of IA in those with higher titers would avoid a coagulopathy.

We are aware that some centers have recently abandoned the use of rituximab before ABOi transplant.18 We have used rituximab from the inception of adult ABOi program based on the Karolinska protocol.19 At present, we believe that complete omission of rituximab remains controversial, and we have therefore continued to incorporate it in a tailored fashion in our pediatric protocol because of the concerns about the risks of rejection.

We did however abandon routine postoperative antibody removal early in our adult program based partly on the experience of others20,21 and have incorporated this in our pediatric program.

The few reports of ABOi kidney transplantation in a pediatric population have shown good graft outcomes when compared with ABO compatible transplants,17 and these strategies have used routine posttransplant antibody removal. Our study shows the natural course of ABO antibody titers posttransplant because antibody removal was not performed routinely. The low risk of rejection in our cohort is comparable to recently reported studies.22 We have not observed adverse effects with the apheresis sessions in any of our patients.

Tailored desensitization is a feasible option, and it should, therefore, be offered to a selected cohort of children in experienced centers. We would recommend it to those pediatric patients with long waiting times on the deceased donor list, those unsuccessful in the living donor kidney sharing scheme or those who urgently require a transplant.

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ACKNOWLEDGMENTS

The authors would like to thank all the staff at Evelina London Children’s Hospital, Great Ormond Street Hospital for Children, Southampton Children’s Hospital and Guy’s and St Thomas’ NHS Foundation Trust, and in particular Tim Maggs (GSTS Pathology) for help with antibody titer measurements; Suzanne Bradley and Katie Knapp (Great Ormond Street Hospital NHS Foundation Trust) and Shuman Haq and Sarah Grylls (Southampton Children’s Hospital) for help in data collection; Liz Wright (Great Ormond Street Hospital NHS Foundation Trust) and Carmen Barton (Evelina London Children’s Hospital) for help with antibody removal.

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